A phase I study of KL590586, a next-generation selective RET inhibitor, in patients with RET-altered solid tumors.
Authors: Qing Zhou, Yi-Long Wu, Xiangqian Zheng, Dapeng Li, Dingzhi Huang, Xingya Li, Anwen Liu, Xia Song, Shanghua Jing, Mingxia Wang, Xicheng Wang, Yongzhong Luo, Yong Song, Yanjun Mi, Jianying Zhou, Yun Fan, Haichuan Su, Tao Huang, Weiwei Ouyang, Junyou Ge
Journal: Journal of Clinical Oncology (2023)

3007 Background: KL590586 (A400/EP0031) is a potent next-generation selective RET inhibitor (SRI) with activity against acquired resistance mutations to first-generation SRIs, and brain metastases (mets). Here we present preliminary data of the phase Ⅰ part from a phase I/II study (KL400-I/II-01, NCT05265091) in patients (pts) with RET-altered advanced tumors to define safety, pharmacokinetics (PK) and efficacy. Methods: The phase Ⅰ of KL400-I/Ⅱ-01 consisted of dose-escalation (Bayesian Optimal Interval design) and dose-expansion. Primary endpoints were to determine the maximum tolerated dose (MTD) and/or Recommended Phase II Dose. Secondary endpoints included safety, PK, objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) as per RECIST 1.1. Results: As of Dec. 30, 2022, 87 pts with RET-altered tumors were treated at 6 doses levels (10 to 120 mg QD). No DLTs were observed, and MTD was not reached. Incidence of treatment-related adverse events (TRAEs, any grade) was 93.1% (81/87), most (74.7%) were grade 1-2, reversible and included (&gt;25%): AST increase (50.6%), ALT increase (48.3%), creatinine increase (33.3%), bilirubin increase (32.2%), constipation (32.2%) and headache (31%). 24.1% of pts had grade ≥3 TRAEs, the most common (occurring in &gt;2% of pts) were ALP increase (2.3%), GGT increase (2.3%), ileus (2.3%). TRAEs led to dose reduction or treatment discontinuation in 4.6% and 6.9% of pts, respectively. Hypertension, QT interval prolongation, platelets decrease and lymphocytes decrease (leading to 1 st gen SRI dose delays and modifications frequently) were rare (&lt;5%) and low-grade. The exposure increased dose-dependently and the mean half-life was found to be 34.1-99.8 h. Clinical responses were observed from 40mg onwards. 69 pts treated at the 40-120mg dose levels (57 NSCLC, 10 MTC, 1 pancreatic cancer, 1 ovarian cancer) were evaluable for efficacy analysis, ORR was 64% (NSCLC, MTC and pancreatic cancer). Most pts (58/69) remained on treatment, with the longest &gt;11 months. The ORR in pts with systemic pretreated NSCLC (median prior treatment: 2, range 1-9, 28% pretreated with anti-PD1/PD-L1 therapy) was 63%(20/32, 1 CR), DCR 91% with median DoR not reached. 9 pts received prior 1 st gen SRI, 7 with tumor shrinkage of -10% to -69%, with 3 PR and 4 SD. 11 pts with brain mets (without radiotherapy):4/5 with measurable brain disease had 100%, 100%, 80%, and 47% shrinkage. Overall CNS DCR was 100%.The ORR in treatment naïve NSCLC was 76% (19/25, 1 CR), DCR 92% and median DoR not reached. 3/4 pts with brain mets (without radiotherapy) had complete or partial disappearance of baseline brain lesions. Conclusions: KL590586 was well-tolerated, and associated with robust clinical activity in RET-altered tumors regardless of tumor type, including NSCLC pts with resistance to1 st gen SRIs and with CNS mets. Pivotal studies are planned. Clinical trial information: NCT05265091 .